TWI419693B - Amine salts of a crth2 antagonist - Google Patents

Description

Amine salt of CRTH2 antagonist

Provided herein are amine salts of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylidinium)benzyl)pyrimidin-5-yl}acetic acid And a preparation method thereof and a pharmaceutical composition. Methods for treating, preventing or ameliorating one or more symptoms of a CRTH2-mediated condition or disease are also provided.

CRTH2 is a G protein-coupled chemoattractant receptor expressed on Th2 cells, eosinophils, and basophils (Nagata et al., J. Immunol. 1999, 162, 1278-1286; Hirai et al., J. Exp. Med., 2001, 193, 255-261). The major inflammatory mediator prostaglandin D ₂ (PGD ₂ ) produced by mast cells is a natural ligand for CRTH2. Recently, it has been shown that CRTH2 is activated by PGD _{2 to} induce migration and activation of Th2 cells and eosinophils, suggesting that CRTH2 may play a pro-inflammatory role in allergic diseases (Hirai et al., J. Exp. Med. 2001, 193, 255). -261; Gervais et al, J. Allergy Clin. Immunol. 2001, 108, 982-988). It has also been shown that there is an increase in circulating T cells expressing CRTH2 in patients with atopic dermatitis, which is related to the severity of the disease (Cosmi et al, Eur. J. Immunol., 2000, 30, 2972-2979; Iwazaki et al. Man, J. Investigative Dermatology, 2002, 119, 609-616). The role of PGD ₂ in triggering and maintaining allergic inflammation has been further demonstrated in the asthma mouse model by showing an overproduction of PGD ₂ by PGD ₂ synthetase in vivo to further aggravate the role of PGD ₂ (Fujitani et al., J. Immunol. 2002) . , 168, 443-449). Thus, CRTH2 antagonists are potentially useful for the treatment of CRTH2-mediated conditions or diseases, such as allergic rhinitis, allergic asthma, bronchoconstriction, atopic dermatitis or systemic inflammatory conditions.

The present invention provides an amine salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylidinium)benzyl)pyrimidin-5-yl}acetic acid , which has the formula I: Or a pharmaceutically acceptable hydrate and solvate thereof. The compound of formula I has been identified as a CRTH2 antagonist (WO 2004/0022218).

In one embodiment, the amine salt comprising an acid of formula I and a pharmaceutically acceptable amine is crystalline.

In another embodiment, the amine salt comprises an acid of formula I and a pharmaceutically acceptable amine other than ethanolamine, triethylamine and hydroxymethylaminomethane.

In another embodiment, {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylideneamino)benzyl)pyrimidin-5-yl} The amine salt of acetic acid is a diamine salt each comprising about 2 moles of an acid of formula I and about 1 mole equivalent of a diamine.

In another embodiment, {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylideneamino)benzyl)pyrimidin-5-yl} The diamine salt of acetic acid is crystalline.

In another embodiment, {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylideneamino)benzyl)pyrimidin-5-yl} The amine salt of acetic acid is a monoamine salt each comprising about 1 mole equivalent of the acid of formula I and about 1 mole equivalent of monoamine.

In another embodiment, {4,6-bis(dimethylamino)-2-(4-(4-(trifluoro)) The monoamine salt of benzylamino)benzyl)pyrimidin-5-yl}acetic acid is crystalline.

Also provided for the preparation of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylidinium)benzyl)pyrimidin-5-yl}acetic acid A method of the amine salt or a pharmaceutically acceptable hydrate or solvate thereof.

In one embodiment, the method comprises reacting {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamide) at a first predetermined temperature Benzyl)pyrimidin-5-yl}acetic acid is reacted with an amine in a solvent.

In another embodiment, the method further comprises precipitating the amine salt at a second predetermined temperature.

In another embodiment, the method comprises the steps of: (a) by making {4,6-bis(dimethylamino)-2-(4-(4-(3) at a first predetermined temperature Fluoromethyl)benzhydrylamino)-benzyl)pyrimidin-5-yl}acetic acid is reacted with an amine in a solvent to produce an amine salt; and (b) the amine salt is precipitated at a second predetermined temperature.

Further provided is an amine comprising {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylidinium)benzyl)pyrimidin-5-yl}acetic acid A pharmaceutical composition of a salt or a pharmaceutically acceptable hydrate or solvate thereof and one or more pharmaceutically acceptable carriers or excipients.

Further, a method for treating, preventing or ameliorating one or more symptoms of a CRTH2-mediated condition or disease comprising administering to a mammal a therapeutically effective amount of {4,6-bis(dimethylamino) An amine salt of 2-(4-(4-(trifluoromethyl)benzylidinoamino)benzyl)pyrimidin-5-yl}acetic acid or a pharmaceutically acceptable hydrate or solvate thereof.

To facilitate an understanding of the disclosures set forth herein, several are defined below the term.

As used herein, the singular forms "" Generally, the nomenclature used herein and the organic chemistry, medicinal chemistry, and pharmacology laboratory procedures described herein are well known and commonly employed in the art. All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains, unless otherwise defined. In the event that there are multiple definitions of the terms herein, unless otherwise stated, the definitions in this section prevail.

The term "antisolvent" refers to a liquid that is added to a solvent to reduce the solubility of the compound in the solvent to cause precipitation of the compound.

The term "subject" refers to an animal including, but not limited to, a primate (eg, a human), a cow, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, or a mouse. Generally, the terms "subject" and "patient" are used interchangeably herein with respect to, for example, a mammalian subject, particularly a human subject.

The term "treating" is meant to include alleviating or eliminating a condition or disease, or one or more symptoms associated with the condition or disease; or alleviating or eradicating the cause of the condition or the disease itself.

The term "prevention" refers to a method of delaying or excluding the onset of a disease and/or its accompanying symptoms, protecting the subject from the disease or reducing the risk of the subject suffering from the disease.

The term "therapeutically effective amount" means a condition or conditions which, when administered, are sufficient to prevent the development of one or more symptoms of the disease, condition or condition being treated, or to some extent alleviate one or more of the symptoms, conditions or conditions being treated. Compound the amount. The term "therapeutically effective amount" also refers to an amount of a compound that elicits a biological or medical response of a tissue, system, animal or human being sought by a researcher, veterinarian, medical physician or clinician.

The term "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier" or "physiologically acceptable excipient" means a pharmaceutical A pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. The components must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation. It must also be suitable for use in contact with human or animal tissues or organs without toxic, irritating, allergic, immunogenic or other problems or complications and commensurate with a reasonable benefit/risk ratio.

The term "naturally occurring" or "native" when used in connection with biological materials such as nucleic acid molecules, polypeptides, host cells, and the like, refers to materials found in nature and not manipulated by humans. Similarly, "non-naturally occurring" or "non-native" refers to materials that are not found in nature or have been altered by structure or synthesis by humans.

The term "CRTH2" refers to the CRTH2 receptor protein or variant thereof, capable of regulating the living PGD ₂ in vitro or in vivo cell response pair. CRTH2 variants include proteins that are substantially homologous to native CRTH2, ie, proteins that have one or more amino acid deletions, insertions or substitutions that are naturally or non-naturally occurring compared to the amino acid sequence of native CRTH2 (eg, CRTH2 derivatives, homologs and fragments). The amino acid sequence of the CRTH2 variant is at least about 80% identical to native CRTH2, at least about 90% identical, or at least about 95% identical.

The term "other PGD ₂ receptor" means other than the prostate prime CRTH2 receptor protein or variant thereof, capable of regulation of PGD ₂ cell responses in vivo or in vitro. "Other PGD ₂ receptors" may be selective for PGD ₂ , such as DP or one or more other prostaglandins. "Other PGD ₂ receptor" variants include proteins that are substantially homologous to a corresponding native prostaglandin receptor other than CRTH2, ie, one or more naturally occurring or non-naturally occurring amino acid deletions, insertions or substitutions. Proteins (eg, derivatives, homologs, and fragments of native prostaglandin receptors other than CRTH2). The amino acid sequence of the native "other PGD ₂ receptor" variant is at least about 80% identical, at least about 90% identical, or at least about 95% identical to the corresponding native "other PGD ₂ receptor."

The term "CRTH2 antagonist" refers to a compound that, for example, partially or completely blocks, reduces, prevents, inhibits, or downregulates the activity of CRTH2 and/or the activity of one or more other PGD ₂ receptors. The term "CRTH2 antagonist" also refers to binding CRTH2 or one or more other PGD ₂ receptors, the activation delay of one or more ₂ or other CRTH2 receptor PGD, a passivation CRTH2 or one or more other PGD ₂ receptors, or A compound that desensitizes CRTH2 or one or more other PGD ₂ receptors. CRTH2 antagonists by interfering the interaction of PGD ₂ with CRTH2 or other PGD ₂ receptor of one or more acts.

The term "CRTH2-mediated condition or disease" and "condition, disorder or disease mediated by CRTH2" refers to a condition, disorder or disease characterized by inappropriate CRTH2 activity (eg, less than or greater than normal CRTH2 activity). Improper CRTH2 functional activity may occur due to increased CRTH2 expression, increased CRTH2 expression, or increased intracellular activation in cells that do not normally exhibit CRTH2, causing, for example, inflammation and immune-related disorders or diseases; or due to decreased CRTH2 performance . The condition, disorder or disease mediated by CRTH2 may be mediated, in whole or in part, by inappropriate CRTH2 activity. In particular, the CRTH2-mediated condition, disorder or disease or one or more other PGD ₂ receptor CRTH2 adjusting conditions to produce a certain effect, disorder or condition or potential condition, or CRTH2 antagonist e.g. The agonist produces some improvement in at least some of the patients treated.

Amine salt

Provided herein are amine salts of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylidinium)benzyl)pyrimidin-5-yl}acetic acid And solvates thereof; and methods for their preparation. Pharmaceutical compositions of such amine salts or solvates thereof and methods for treating, preventing or ameliorating one or more symptoms of a CRTH2-mediated condition or disease are also provided.

According to an embodiment, {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylidinium)benzyl)-pyrimidin-5-yl} is provided A pharmaceutically acceptable amine salt of acetic acid comprising an acid of formula I and a pharmaceutically acceptable amine. In another embodiment, a pharmaceutically acceptable {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylideneamino)benzyl group is provided a solvate of a crystalline amine salt of pyrimidine-5-yl}acetic acid comprising an acid of formula I, a pharmaceutically acceptable amine, and a solvent.

In certain embodiments, the amine salt or solvate thereof has an acid to amine molar ratio of the formula I of from about 0.5 to about 10, from 0.5 to about 5, from about 0.5 to about 3, from about 0.5 to about 2, or about 0.8. To about 1.2 or about 1.

In certain embodiments, the solvate of the amine salt provided herein has a molar ratio of acid to solvent of Formula I of from about 0.1 to about 2, from about 0.2 to about 1 or about 0.3 to About 0.5 or about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9 or about 1.

Amines suitable for use in the amine salts or solvates thereof as provided herein include, but are not limited to, primary amines including methylamine, ethylamine, ethanolamine, hydroxy(hydroxymethyl)aminomethane and ethylenediamine; Amines, including dimethylamine, diethylamine, diisopropylamine, dibutylamine, di-second butanamine, dicyclohexylamine, diethanolamine, meglumine, pyrrolidine, piperidine, piperazine and dibenzyl Ethylenediamine; tertiary amines, including trimethylamine, triethylamine, triethanolamine, and 1-(2-hydroxyethyl)-pyrrolidine; quaternary ammonium, including choline, tetramethylammonium, and tetraethylammonium. For a review of other amines, see "Handbook of Pharmaceutical Salts: Properties, Selection and Use", Stahl and Wermuth, Wiley-VCH, 2002.

In one embodiment, the pharmaceutically acceptable amine is a diamine. The pharmaceutically acceptable diamine has first and second amine groups, each of which is independently a primary, secondary or tertiary amine group, or a quaternary ammonium group. Suitable diamines for the diamine salt include, but are not limited to, ethylenediamine, piperazine, and bisbenzylethylenediamine. {1,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylideneamino)benzyl)-pyrimidine for 1 molar equivalent of diamine The diamine salt of -5-yl}acetic acid comprises from about 1 to about 3, from about 1.5 to about 2.5, from about 1.75 to about 2.25 or about 2 molar equivalents of the acid of formula I.

In one of the group diamine salts of this embodiment, the first amine group of the diamine is a primary amine group and the second amine group is independently a primary, secondary or tertiary amine group, or a quaternary ammonium. In another group of diamine salts, the first amine group is independently a secondary amine group and the second amine group is a primary, secondary or tertiary amine group, or a quaternary ammonium. In another group of diamine salts, the first amine group is independently a tertiary amine group and the second amine group is a first stage, A secondary or tertiary amine group, or a quaternary ammonium. In another group of diamine salts, the first amine group is a quaternary ammonium and the second amine group is independently a primary, secondary or tertiary amine group, or a quaternary ammonium.

In another embodiment, the pharmaceutically acceptable amine is a diamine having two primary amine groups. For a 1 molar equivalent of a primary diamine, the primary diamine salt of an acid of Formula I comprises from about 1 to about 3, from about 1.5 to about 2.5, from about 1.75 to about 2.25, or about 2 molar equivalents of the acid of formula I .

In another embodiment, the primary diamine is ethylene diamine. {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylidinium)-benzyl as assessed by ¹ H NMR spectrum (Figure 1) The ethylenediamine salt of pyrimidine-5-yl}acetic acid comprises about 2 moles of an acid of formula I and about 1 mole equivalent of ethylenediamine.

In another embodiment, the acid ethylenediamine salt of formula I is crystalline. The crystalline ethylenediamine salt has an XRP diffraction pattern substantially as shown in FIG. In particular, the crystalline ethylenediamine salt has a characteristic XRP diffraction peak at an angle of about 5.9 2 2θ. Further, the crystalline ethylenediamine salt has a DSC thermogram as generally shown in FIG. The crystalline ethylenediamine salt has an endotherm having a peak temperature of about 123 ° C and an onset temperature of 114 ° C or a peak temperature of about 216 ° C and an onset temperature of about 212 ° C. Alternatively, the crystalline ethylenediamine salt has an endotherm having a peak temperature of about 123 ° C and an onset temperature of 114 ° C and a peak temperature of about 216 ° C and an onset temperature of about 212 ° C.

In another embodiment, a crystalline ethylenediamine salt of an acid of Formula I is provided herein. Its solvate has an XRP diffraction pattern substantially as shown in Figure 2. In particular, the solvate has a characteristic XRP diffraction peak at a 2 theta angle of about 5.9 Torr. In addition, the solvate has a DSC thermal score substantially as shown in Figure 3. Analysis of the map. The solvate has an endotherm having a peak temperature of about 123 ° C and an onset temperature of 114 ° C or a peak temperature of about 216 ° C and an onset temperature of about 212 ° C. Alternatively, the solvate has an endotherm having a peak temperature of about 123 ° C and an onset temperature of 114 ° C and a peak temperature of about 216 ° C and an onset temperature of about 212 ° C.

In one embodiment, the solvate exhibits from about 1% to about 10% (including but not limited to) about 1%, about 2%, about 3%, about 4%, about 5 between 125 ° C and 150 ° C. %, about 6%, about 7%, about 8%, about 9%, and about 10%) weight loss. In another embodiment, the solvate exhibits a 2%, about 3%, about 4%, or about 5% weight loss between 125 °C and 150 °C.

In one embodiment, the solvate contains from about 0.1 to about 2, from about 0.2 to about 1 or from about 0.3 to about 0.5; or from about 0.1, about 0.2, about 0.3, about 0.4, for each mole equivalent of the amine salt. A solvent of about 0.5, about 0.6, about 0.7, about 0.8, about 0.9 or about 1 mole equivalent. In another embodiment, the solvate contains from about 0.3 to about 0.5 mole equivalents of solvent per mole equivalent of amine salt. In another embodiment, the solvate contains about 0.3 mole equivalents of solvent per mole equivalent of the amine salt. In another embodiment, the solvate contains about 0.4 molar equivalents of solvent per mole equivalent of the amine salt. In another embodiment, the solvate contains about 0.5 mole equivalents of solvent per mole equivalent of the amine salt.

In one embodiment, the solvent in the solvate is an alcohol, including but not limited to methanol, ethanol, isopropanol (IPA), 1-propanol, 1-butanol, 2-butanol, third Alcohol, 3-methyl-1-butanol, 1-pentanol, 2-methoxyethanol, 2-ethoxyethanol and ethylene glycol. In another embodiment, the solvent is ethanol.

In another embodiment, the pharmaceutically acceptable amine is a diamine having two secondary amine groups. For a 1 molar equivalent of a secondary diamine, the secondary diamine salt of an acid of Formula I comprises from about 1 to about 3, from about 1.5 to about 2.5, from about 1.75 to about 2.25, or about 2 molar equivalents of the acid of formula I .

In another embodiment, the secondary diamine is piperazine. {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylideneamino)benzyl) as assessed by ¹ H NMR spectrum (Figure 6) The piperazine salt of pyrimidin-5-yl}acetic acid comprises about 2 moles of an acid of formula I and about 1 mole equivalent of piperazine.

In another embodiment, the piperazine salt is crystalline. The crystalline piperazine salt has an XRP diffraction pattern substantially as shown in FIG. In one embodiment, the piperazine salt has a characteristic XRP diffraction peak at a 2 theta angle of about 10.7, 15.9, 22.3, and 24.0 Å. In another embodiment, the piperazine salt has a characteristic XRP diffraction peak at a 2 theta angle of about 10.7, 15.9, 22.3, or 24.0 Å. In another embodiment, the crystalline piperazine salt has a DSC thermogram as generally shown in FIG. In another embodiment, the crystalline piperazine salt has an endotherm having a peak temperature of about 203 ° C and an onset temperature of about 197 ° C or a peak temperature of about 223 ° C and an onset temperature of about 219 ° C. In an alternative embodiment, the crystalline piperazine salt has an endotherm having a peak temperature of about 203 ° C and an onset temperature of about 197 ° C and a peak temperature of about 223 ° C and an onset temperature of about 219 ° C.

In another embodiment, the secondary diamine is bisbenzylethylenediamine. {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylideneamino)benzyl) as assessed by ¹ H NMR spectrum (Figure 11) The bisbenzylethylenediamine salt of pyrimidin-5-yl}acetic acid comprises about 2 moles of an acid of formula I and about 1 mole equivalent of bisbenzylethylenediamine.

In another embodiment, the bisbenzylethylenediamine salt is crystalline having an XRP diffraction pattern substantially as shown in FIG. In one embodiment, the bisbenzylethylenediamine salt has a characteristic XRP diffraction peak at a 2 theta angle of about 8.0, 11.5, 16.0, 17.5, and 23.4 Torr. In another embodiment, the bisbenzylethylenediamine salt has a characteristic XRP diffraction peak at a 2 theta angle of about 8.0, 11.5, 16.0, 17.5, or 23.4 Torr. In another embodiment, the crystalline bisbenzylethylenediamine salt has a DSC thermogram as generally shown in FIG. In an alternative embodiment, the crystalline bisbenzylethylenediamine salt has an endotherm having a peak temperature of about 156 °C and an onset temperature of about 154 °C.

In another embodiment, the amine is a monoamine. {1,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylideneamino)benzyl)pyrimidine-5- for 1 molar equivalent of monoamine The monoamine salt of acetic acid comprises from about 0.5 to about 1.5, from about 0.75 to about 1.25, or about 1 mole equivalent of the acid of formula I.

In the monoamine salt of one of the examples, the monoamine of the monoamine salt has a primary amine group. In another group of monoamine salts, the monoamine has a secondary amine group. In another group of monoamine salts, the monoamine has a tertiary amine group. In another group of monoamine salts, the monoamine has a quaternary ammonium group.

In an alternative embodiment, the amine is choline. {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylideneamino)benzyl) as assessed by ¹ H NMR spectrum (Figure 15) The choline salt of pyrimidin-5-yl}acetate comprises about 1 mole equivalent of the acid of formula I and about 1 mole equivalent of choline.

In another embodiment, the choline salt of the acid of Formula I is crystalline having an XRP diffraction pattern substantially as shown in FIG. In one embodiment, the choline salt has characteristics at 2θ angles of about 6.5, 19.6, 20.0, 21.9, and 26.4 ∘. XRP diffraction peaks. In another embodiment, the choline salt has a characteristic XRP diffraction peak at a 2 theta angle of about 6.5, 19.6, 20.0, 21.9, or 26.4. In another embodiment, the crystalline choline salt has a DSC thermogram as generally shown in FIG. In an alternative embodiment, the crystalline choline salt has an endotherm having a peak temperature of about 195 °C and an onset temperature of about 193 °C.

It should be understood that the values of the peaks of the X-ray powder diffraction pattern between instruments or between samples may be slightly different, and therefore the values mentioned should not be construed as absolute, but rather have permissible variability, such as 0.1 ∘, which is United State Pharmacopeia, 2007, pp. 387-389.

Preparation

A process for the preparation of an amine salt of an acid of formula (I) is also provided. In one embodiment, the method comprises reacting {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamide) at a first predetermined temperature Benzyl)pyrimidin-5-yl}acetic acid is reacted with an amine in a solvent. In another embodiment, the method further comprises precipitating the amine salt at a second predetermined temperature.

In an alternative embodiment, the method comprises the steps of: (a) by making {4,6-bis(dimethylamino)-2-(4-(4-(3) at a first predetermined temperature Fluoromethyl)benzhydrylamino)-benzyl)pyrimidin-5-yl}acetic acid is reacted with an amine in a solvent to produce an amine salt; and (b) the amine salt is precipitated at a second predetermined temperature.

Suitable solvents for the preparation of the amine salt of the acid of formula I include, but are not limited to, hydrocarbons including petroleum ether, pentane, hexane, heptane, octane, isooctane, cyclopentane, cyclohexane, methyl Cyclohexane, benzene, toluene, xylene, tetralin and cumene; chlorinated hydrocarbons, including dichloromethane (DCM), 1,2-dichloroethane, 1,1-dichloroethylene, 1, 2-Dichloroethylene, chloroform, trichloroethane, trichloroethylene, Carbon tetrachloride, chlorobenzene and trifluoromethylbenzene; alcohols, including methanol, ethanol, isopropanol (IPA), 1-propanol, 1-butanol, 2-butanol, tert-butanol, 3- Methyl-1-butanol, 1-pentanol, 2-methoxyethanol, 2-ethoxyethanol and ethylene glycol; ethers, including diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE ), diphenyl ether, 1,2-dimethoxyethane, bis(2-methoxyethyl)ether, 1,1-dimethoxymethane, 2,2-dimethoxypropane, and benzene Methyl ether; ketones, including acetone, methyl ethyl ketone, methyl ethyl ketone (MEK), methyl isopropanone, methyl butyl ketone and methyl isobutyl ketone (MIBK); esters, including methyl acetate, formic acid Ethyl ester, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate and butyl acetate; carbonates, including ethylene carbonate and propylene carbonate; guanamine, including formamide, N, N - dimethylformamide (DMF) and N,N-dimethylacetamide; nitrile, including acetonitrile (ACN); hydrazine, such as dimethyl hydrazine (DMSO); hydrazine, such as cyclobutyl hydrazine; Nitro compounds such as nitromethane and nitrobenzene; heterocycles such as N-methylpyrrolidone, 2-methyltetrahydrofuran, tetrahydrogen Furan (THF), dioxane, and pyridine; carboxylic acids, such as acetic acid, trichloroacetic acid and trifluoroacetic acid; phosphorus acyl amines, acyl amines such as hexamethylphosphoramide; carbon disulfide; water; and mixtures thereof.

In certain embodiments, the amine salt formation reaction (i.e., step a) is carried out at a temperature of from about -10 to about 150 ° C, from about 10 to about 110 ° C, or from about 20 to about 100 ° C. In one embodiment, the solvent is acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, N, N-dimethylformamide, dimethyl hydrazine, lower alkanol (eg methanol, ethanol) , n-propanol, isopropanol, second butanol or 2-methoxyethanol), methyl acetate, ethyl acetate, ethyl formate, isopropyl acetate, isobutyl acetate, chloroform, dichloromethane, Methyl tertiary butyl ether, tetrahydrofuran Norm, 1,4-dioxane, petroleum ether, hexane, heptane, toluene, water or a mixture thereof. In another embodiment, the solvent is a 1 to 5 carbon lower alkanol such as methanol, ethanol, propanol, isopropanol, second butanol, 2-methoxyethanol or a mixture thereof.

In certain embodiments, the amine salt formation reaction is carried out in the presence of an excess of amine to maximize the reaction yield. The molar ratio of the amine group on the amine to the acid of formula I is not less than about 1.01, not less than about 1.05, not less than about 1.1, not less than about 1.2, from about 1.05 to about 10, from about 1.1 to about 5 Or about 1.2 to about 2.5.

In certain embodiments, the salt formation reaction is carried out in solution, i.e., both the acid of the formula I and the amine are dissolved in the solvent. In certain embodiments, the salt formation reaction is carried out as a slurry mixture of an acid of formula I and an amine in a solvent. In this case, the acid of formula I is not completely dissolved and the amine is completely dissolved.

In certain embodiments, the amine salt formed in the amine salt formation reaction step may be precipitated from the reaction solution or slurry mixture using conventional methods, including, but not limited to, cooling, freezing, solvent evaporation, Add an anti-solvent or add it back to the anti-solvent. The precipitation step can be carried out at a temperature of from about -50 to about 100 ° C, from about -30 to about 50 ° C, or from about -10 to about 30 ° C. To accelerate the precipitation (crystallization) step, the method may further comprise the step of inoculating the reaction solution or mixture. The method may also comprise a separation step wherein the precipitation may be separated by conventional methods such as filtration and centrifugation followed by solvent washing followed by drying.

In one embodiment, 4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)-benzamide)benzyl)pyrimidine is made by (a) -5-yl}acetic acid is reacted with an amine in a lower alkanol such as ethanol at a high temperature to produce a clear reaction solution. Prepare the amine salt. When the amine is a diamine, the molar ratio of the diamine molecule to the acid of formula I in the reaction solution is not less than about 0.505, not less than about 0.525, not less than about 0.55 or not less than about 0.60; At about 10 or about 100. When the amine is a monoamine, the molar ratio of the monoamine molecule to the acid of formula I in the reaction solution is not less than about 1.01, not less than about 1.05, not less than about 1.1; but not more than about 10 or about 100. .

The amine salt can be precipitated by cooling the reaction solution to room temperature or below or by evaporation of the solvent. The amine salt precipitate can also be formed by adding an anti-solvent to the reaction solution or by adding a reaction solution to the anti-solvent.

Suitable antisolvents include, but are not limited to, hydrocarbons including petroleum ether, pentane, hexane, heptane, octane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, benzene, toluene, Toluene, tetralin and cumene; chlorinated hydrocarbons, including dichloromethane, 1,2-dichloroethane, 1,1-dichloroethylene, 1,2-dichloroethylene, chloroform, trichloroethane , trichloroethylene, carbon tetrachloride, chlorobenzene and trifluoromethylbenzene; alcohols, including isopropanol, 1-propanol, 1-butanol, 2-butanol, tert-butanol, 3-methyl 1-butanol, 1-pentanol, 2-ethoxyethanol and ethylene glycol; ethers, including diethyl ether, diisopropyl ether, methyl tert-butyl ether, diphenyl ether, 1,2-dimethyl Oxyethane, bis(2-methoxyethyl)ether, 1,1-dimethoxymethane, 2,2-dimethoxypropane and anisole; ketones, including butanone, methyl Isoacetone, methyl butyl ketone and methyl isobutyl ketone; esters, including methyl acetate, ethyl formate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate and butyl acetate; Ester, including ethylene carbonate and propylene carbonate; nitro compounds, including nitromethane and nitrobenzene Heterocyclyl; carbon disulfide; water; and mixtures thereof.

When two solvents are used as the solvent/antisolvent pair, the amine salt of the acid of formula I has a higher solubility in the solvent than in the antisolvent. The solvent and antisolvent in the solvent/antisolvent pair are at least partially miscible, as appropriate.

In another embodiment, {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)-benzylideneamino)benzyl is rendered by (a) The pyrimidine-5-yl}acetic acid is reacted with an amine in a slurry such as ethanol at room temperature or at elevated temperature to prepare an amine salt. After the reaction, the solid amine salt can be recovered by cooling, evaporating the solvent from the slurry reaction mixture or adding an anti-solvent to the slurry reaction mixture.

To accelerate the precipitation (crystallization) step, the method may further comprise the step of inoculating the reaction solution or mixture before or during the start of the precipitation step. The amount of seed crystal added exceeds the amount of saturation in the solvent used so that undissolved seed crystals are present in the reaction solution.

Other salt forming methods are also applicable to the present invention. For example, an amine salt of an acid of formula I can be prepared by converting a salt of an acid (e.g., a sodium or potassium salt) to an amine salt via cation exchange using a cation exchange column. The solid {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)-benzamide) can also be physically obtained by the absence of a solvent. The benzyl)pyrimidin-5-yl}acetic acid and the amine are ground together to produce the amine salt of the acid of formula I.

In addition to precipitation and crystallization, the solid amine salts provided herein can also be prepared using conventional methods known to those skilled in the art, including spray drying, drum drying, freeze drying, and melt crystallization.

Pharmaceutical composition

Also provided is a composition comprising {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylidinium)-benzyl)pyrimidin-5-yl}acetic acid Amine salt or its medicinal A pharmaceutical composition of an acceptable hydrate or solvate (as an active pharmaceutical ingredient) with one or more pharmaceutically acceptable carriers or excipients. The choice of excipient will depend to a large extent on factors such as the particular mode of administration, the effect of the excipient on the solubility and stability of the active ingredient, and the nature of the dosage form.

The pharmaceutical compositions provided herein can be provided in unit dosage form or in multiple dosage forms. As used herein, unit dosage form refers to physically discrete units of such art that are suitable for administration to human and animal subjects and are individually packaged. Each unit dose contains a predetermined amount of the active ingredient sufficient to produce the desired therapeutic effect together with the desired pharmaceutical carrier or excipient. Examples of unit dosage forms include ampoules, syringes, and individually packaged tablets and capsules. Unit dosage forms can be administered in proportional portions or in multiple portions. Multiple dosage forms are a plurality of identical unit dosage forms that are packaged in a single container in a separate unit dosage form. Examples of multiple dosage forms include vials, lozenges or capsules or pints or gallons.

The amine salt of the acid of formula I provided herein can be administered alone or in combination with one or more other compounds, one or more other active ingredients provided herein. Pharmaceutical compositions comprising the amine salts provided herein can be formulated into a variety of dosage forms for oral, parenteral, and topical administration. The pharmaceutical compositions can also be formulated as modified release dosage forms including delayed, sustained release, extended, sustained, pulsatile, controlled, accelerated, and rapid, targeted, stylized release, and gastric retention dosage forms. Such dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see Remington: The Science and Practice of Pharmacy , supra; Modified-Release Drug Deliver Technology , Rathbone et al., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2002 ; Vol. 126).

The pharmaceutical compositions provided herein can be administered in multiple doses or at intervals of time. It will be appreciated that the precise dosage and duration of treatment will vary with the age, weight and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro testing or diagnostic data. It should be further appreciated that for any particular individual, the particular dosage regimen should be adjusted over time based on the individual's needs and the professional judgment of the person administering or supervising the formulation.

A. Oral administration

The pharmaceutical compositions provided herein can be provided for oral administration in a solid, semi-solid or liquid dosage form. As used herein, oral administration also includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, lozenges, capsules, pills, tablets, buccal preparations, tablets, cachets, pellets, medicated chewing gum, granules, lumps, effervescent or non-effervescent powders or Granules, solutions, emulsions, suspensions, solutions, wafers, dispersions, elixirs and syrups. In addition to the active ingredient, the pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or excipients including, but not limited to, binders, fillers, diluents, disintegrating agents, wetting agents, lubricating agents Agents, glidants, colorants, dye migration inhibitors, sweeteners and flavoring agents.

The binder or granulating agent imparts adhesion to the tablet to ensure that the tablet remains intact after compression. Suitable binders or granulating agents include, but are not limited to, starches such as corn starch, potato starch and pregelatinized starch (eg STARCH 1500); gelatin; sugars such as sucrose, dextrose, dextrose, molasses and lactose; Natural and synthetic gums such as acacia, alginic acid, alginic acid Salt, Irish moss extract, Panwar gum, ghatti gum, isabgol pod mucus, carboxymethylcellulose, methylcellulose, polyethylene Pyrrolidone (PVP), Veegum, larch arabinogalactan, powdered tragacanth and guar; cellulose, such as ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose , sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline cellulose, such as AVICEL- PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrose, kaolin, mannitol, citric acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. . In the pharmaceutical compositions provided herein, the binder or filler may comprise from about 50 to about 99% by weight.

Suitable diluents include, but are not limited to, calcium hydrogen phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, anhydrous starch, and powdered sugar. Certain diluents such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient amounts, can impart certain properties to the compressed lozenges that allow disintegration in the mouth by chewing. These compressed tablets are useful as chewable tablets.

Suitable disintegrants include, but are not limited to, agar; bentonite; cellulose, such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginic acid; gums, such as guar gum and weige Muc HV; citrus slag; cross-linked cellulose, such as croscarmellose; cross-linking polymerization Such as cross-linked polyvinylpyrrolidone; cross-linked starch; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starch, such as corn starch, potato starch, tapioca starch and pre- Gelatinized starch; clay; aligns; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein will vary with the type of formulation and can be readily discernible to those of ordinary skill in the art. The pharmaceutical compositions provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.

Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols such as glycerol oleate and polyethylene Alcohol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; zinc stearate; ethyl oleate; Laurel ethyl ester; agar; starch; stone pine; cerium oxide or tannin, such as AEROSIL 200 (WR Grace Co., Baltimore, MD) and CAB-O-SIL (Bobot, MA Cabot Co.); and mixtures thereof. The pharmaceutical compositions provided herein may contain from about 0.1 to about 5% by weight of a lubricant.

Suitable glidants include colloidal cerium oxide, CAB-O-SIL (Bobot, MA Cabot Co.) and non-asbestos talc. Colorants include any of the approved, certified water soluble FD&C dyes and water insoluble FD&C dyes (suspended on alumina hydrate) as well as lakes and mixtures thereof. A lake is a combination of insoluble forms of a dye by adsorbing a water-soluble dye to a hydrated oxide of a heavy metal. Flavoring agents include natural flavorings extracted from plants such as fruits and synthetic blends of compounds that produce a pleasant taste, such as peppermint and methyl salicylate. Sweeteners include sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners such as saccharin and aspartame. Suitable emulsifiers include gelatin, gum arabic, tragacanth, bentonite and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN) 20), polyoxyethylene sorbitan monooleate 80 (TWEEN 80) and triethanolamine oleate. Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, vegas gum, gum arabic, sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Preservatives include glycerin, methylparaben and propylparaben, benzoic acid additives, sodium benzoate and ethanol. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene dodecyl ether. Solvents include glycerin, sorbitol, ethanol, and syrups. Examples of non-aqueous liquids used in the emulsion include mineral oil and cottonseed oil. Organic acids include citric acid and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.

It will be appreciated that many carriers and excipients may provide several functions even within the same formulation.

The pharmaceutical compositions provided herein can be provided in the form of a compressed tablet, a lozenge, a chewable buccal, a rapidly dissolving lozenge, a reconstituted lozenge or an enteric lozenge, a sugar coating or a film lozenge. Enteric coated tablets are compressed tablets which are coated with a substance which is resistant to gastric acid but which dissolves or disintegrates in the intestine to protect the active ingredient from the acidic environment of the stomach. Casings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac and phthalate acetate Acid cellulose. A dragee is a compressed lozenge surrounded by a sugar coating that can be beneficial to mask unpleasant taste or odor and protect the tablet from oxidation. Film tableting agents are compressed tablets coated with a thin layer or film of a water soluble material. Film coats include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. The film coat imparts the same general characteristics as the sugar coat. Compressed tablets are compressed tablets prepared by more than one compression cycle, including layered tablets and compressed or dry coated tablets.

The tablet dosage forms may be prepared separately from the active ingredient in powder, crystalline or granular form or in combination with one or more carriers or excipients described herein, such carriers or excipients. These include binders, disintegrants, controlled release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially suitable for forming chewable tablets and buccal formulations.

The pharmaceutical compositions provided herein may be provided in the form of soft or hard capsules made of gelatin, methylcellulose, starch or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFC), consist of two parts, one part sliding over the other part to completely seal the active ingredient. Soft elastic capsules (SEC) are soft spherical shells, such as gelatin shells, which are plasticized by the addition of glycerin, sorbitol or similar polyols. The soft gelatin shell can contain a preservative to prevent microbial growth. Suitable preservatives are those as described herein, including methylparaben and propylparaben and sorbic acid. The liquid, semi-solid, and solid dosage forms provided herein can be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. It can be prepared as described in U.S. Patent Nos. 4,328,245, 4,409,239 and 4,410,545. Liquid capsule. Capsules may also be coated as known to those skilled in the art to improve or maintain dissolution of the active ingredient.

The pharmaceutical compositions provided herein can be provided in liquid and semi-solid dosage forms including emulsions, solutions, suspensions, elixirs, and syrups. The emulsion is a two-phase system in which one liquid is dispersed in the form of small droplets in another liquid, which may be of the oil-in-water or water-in-oil type. The emulsion may include a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions may include pharmaceutically acceptable suspending agents and preservatives. The aqueous alcohol solution may comprise a pharmaceutically acceptable acetal such as a bis (lower alkyl) acetal of a lower alkyl aldehyde (the term "low carbon" means that the alkyl group has between 1 and 6 carbon atoms. For example, acetaldehyde diethanol acetal; and a water miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Tinctures are clear, sweet and watery solutions. A syrup is a concentrated aqueous solution of a sugar such as sucrose and may also contain a preservative. For liquid dosage forms, for example, a sufficient amount of a pharmaceutically acceptable liquid carrier (e.g., water) can be used to dilute the solution in the polyethylene glycol so that it can be conveniently metered for administration.

Other suitable liquid and semi-solid dosage forms include, but are not limited to, containing the active ingredients provided herein and dialkylated monoalkylene glycols or polyalkylene glycols (including 1,2-dimethoxymethane, diethylene glycol) Alcohol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750- Dimethyl ether, of which 350, 550 and 750 are referred to as the approximate average molecular weight of polyethylene glycol). These formulations may further comprise one or more antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamins E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters , and dithiocarbamate.

The pharmaceutical compositions provided herein for oral administration can also be provided in the form of liposomes, micelles, microspheres or nanosystems. The microcyte dosage form can be prepared as described in U.S. Patent No. 6,350,458.

The pharmaceutical compositions provided herein can be provided in the form of non-effervescent or effervescent granules and powders to be formulated as a liquid dosage form. Pharmaceutically acceptable carriers and excipients for non-effervescent granules or powders may include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients for effervescent granules or powders may include organic acids and carbon dioxide sources.

Coloring and flavoring agents can be used in all of the above dosage forms.

The pharmaceutical compositions provided herein can be formulated as immediate or modified release dosage forms, including delayed, sustained, pulsed, controlled, targeted, and stylized release forms.

Provided herein, the pharmaceutical composition can be without compromising the desired effect of other active ingredients or therapeutic effect of the substance desired and supplement (such as antacids, proton pump inhibitors and H ₂ - receptor antagonist) together with Provisioning.

B. Parenteral administration

The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion or implantation for topical or systemic administration. Parenteral administration, as used herein, includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.

The pharmaceutical compositions provided herein may be formulated for any dosage form for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and suitable for dissolving or suspending in a liquid prior to injection. The solid form in the middle. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of medicine (see Remington: The Science and Practice of Pharmacy , supra).

Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles. Antimicrobial or preservatives, stabilizers, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, Chelating agents, cryoprotectants, lyoprotectants, thickeners, pH adjusters, and inert gases.

Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic glucose injection, sterile water injection, Dextrose and lactated Ringer's injection. Non-aqueous vehicles include, but are not limited to, plant-derived non-volatile oils, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil And coconut oil chain triglyceride and palm seed oil. Water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycols (eg, polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl -2-pyrrolidone, dimethylacetamide and dimethylhydrazine.

Suitable antimicrobials or preservatives include, but are not limited to, phenols, cresols, mercury preparations, benzyl alcohol, chlorobutanol, methyl paraben and propyl paraben, thimerosal, benzalkonium chloride , benzethonium chloride, methyl p-hydroxybenzoate and propyl p-hydroxybenzoate and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphates and citrates. Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable chelating agents include, but are not limited to, EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutylether-beta-cyclodextrin, and sulfobutyl Ether 7-β-cyclodextrin (CAPTISOL ^® , CyDex, Lenexa, KS).

The pharmaceutical compositions provided herein can be formulated for single or multiple dose administration. A single dose formulation is packaged in an ampoule, vial or syringe. Multi-dose parenteral formulations must contain an antimicrobial agent at a bacteriostatic or fungistatic concentration. All parenteral formulations must be sterile as known and practiced in the art.

In one embodiment, a pharmaceutical composition is provided in the form of a ready-to-use sterile solution. In another embodiment, a pharmaceutical composition (including lyophilized powder and a lozenge for injection) in the form of a sterile dry soluble product to be formulated with a vehicle prior to use is provided. In another embodiment, a ready-to-use sterile suspension is provided A pharmaceutical composition in the form of a float. In another embodiment, a pharmaceutical composition is provided in the form of a sterile dry insoluble product to be formulated with a vehicle prior to use. In another embodiment, a pharmaceutical composition in the form of a ready-to-use sterile emulsion is provided.

The pharmaceutical compositions provided herein can be formulated as immediate or modified release dosage forms, including delayed, sustained, pulsed, controlled, targeted, and stylized release forms.

The pharmaceutical compositions can be formulated as suspensions, solids, semi-solids or shaken liquids for administration in the form of an implanted reservoir. In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid internal matrix surrounded by an outer polymeric film that is insoluble in body fluids but allows the active ingredients in the pharmaceutical composition to diffuse through.

Suitable internal substrates include polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene Diene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, polyoxyxene rubber, polydimethylsiloxane, polyoxycarbonate copolymer, hydrophilic polymer (such as acrylic acid) And hydrogel of methacrylic acid ester, collagen, cross-linked polyvinyl alcohol and cross-linked partially hydrolyzed polyvinyl acetate).

Suitable external polymeric films include polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, polyoxyxene rubbers, polydimethyl siloxanes, neoprene, Chlorinated polyethylene, polyvinyl chloride, vinyl acetate with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, watch Chlorohydrin rubber, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer.

C. Topical administration

The pharmaceutical compositions provided herein can be topically administered to the skin, orifice or mucosa. As used herein, topical administration includes skin (inner), conjunctiva, intracorneal, intraocular, ocular, otic, transdermal, nasal, transvaginal, urethral, respiratory, and rectal administration.

The pharmaceutical compositions provided herein can be formulated into any dosage form suitable for topical or systemic effects, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, Tinctures, lotions, suspensions, elixirs, pastes, foams, films, aerosols, infusions, sprays, suppositories, bandages, transdermal patches. The topical formulations of the pharmaceutical compositions provided herein may also comprise liposomes, micelles, microspheres, nanosystems, and mixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, anti-microbial growth resistance Microbial or preservatives, stabilizers, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, chelating agents, penetration enhancers , cryoprotectants, lyoprotectants, thickeners and inert gases.

Also by electroporation, iontophoresis, phonophoresis ultra sound, ultrasonic method electroosmosis and microneedle or needle-free injection (such as ^{POWDERJECT TM (Chiron Corp., Emeryville,} CA) and BIOJECT ^TM (Bioject Medical Technologies Inc. , Tualatin, OR)) topical administration of pharmaceutical compositions.

The pharmaceutical compositions provided herein can be provided in the form of ointments, creams and gels. Suitable ointment vehicles include oily or hydrocarbon based agents including lard, benzoinized lard, olive oil, cottonseed oil, white petrolatum and plastibase; emulsifiable or absorbing bases such as hydrophilic petrolatum, hydroxyl sulfate Hard fat and anhydrous lanolin; water-removable bases such as hydrophilic ointments; water-soluble ointment bases, including polyethylene glycols of different molecular weights; emulsion bases, water-in-oil (W/O) emulsions or water bags Oil (O/W) emulsions including cetyl alcohol, glyceryl monostearate, lanolin and stearic acid (see Remington: The Science and Practice of Pharmacy , supra). These agents are emollients, but usually require the addition of antioxidants and preservatives.

Suitable cream bases can be oil-in-water or water-in-oil. The cream vehicle can be water washable and contains an oil phase, an emulsifier, and an aqueous phase. The oil phase is also referred to as the "internal" phase, which is typically composed of petrolatum and fatty alcohols such as cetyl alcohol or stearyl alcohol. The volume of the aqueous phase usually (but not necessarily) exceeds the oil phase and usually contains a humectant. The emulsifier in the cream formulation can be a nonionic, anionic, cationic or amphoteric surfactant.

The gel is a semi-solid, suspension type system. Single phase gels contain organic macromolecules that are substantially uniformly distributed in the liquid carrier. Suitable gelling agents include crosslinked acrylic polymers such as carbomers; carboxyl-terminated alkyl groups, Carbopol®; hydrophilic polymers such as polyethylene oxide, polyethylene oxide-polyoxypropylene copolymers and polyethylene. Alcohol; cellulosic polymers such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate and methylcellulose; gums such as scutellaria gum And Sanxianjiao; sodium alginate; and gelatin. To prepare a uniform gel, a dispersing agent such as ethanol or glycerin may be added, or the gelling agent may be dispersed by wet milling, mechanical mixing, and/or stirring.

The pharmaceutical composition provided herein can be used for rectal, transurethral, vaginal or transvaginal suppositories, pessaries, probes, lozenges or poultices, pastes, powders, dressings, creams, plasters, contraceptives. Administration in the form of a drug, ointment, solution, emulsion, suspension, tampon, gel, foam, spray or enemas. Such dosage forms can be made using conventional methods as described in Remington: The Science and Practice of Pharmacy (supra).

Rectal, urethral and vaginal suppositories are solids suitable for insertion into the body orifice which are solid at ambient temperature but melt or soften at body temperature to release the active ingredient within the orifice. Pharmaceutically acceptable carriers for rectal and vaginal suppositories include vehicles such as sclerosing agents which, when formulated with the pharmaceutical compositions provided herein, produce a melting point near body temperature; and as described herein Oxidants, including bisulfite and sodium metabisulfite. Suitable vehicles include, but are not limited to, cocoa butter (cocoa butter), glycerin-gelatin, polyethylene glycol (polyoxyethylene glycol), cetyl wax, paraffin wax, white wax and yellow wax, and mono-, di- and A suitable mixture of triglycerides, a hydrogel such as polyvinyl alcohol, hydroxyethyl methacrylate, polyacrylic acid; glycerinated gelatin. A combination of various vehicles can be used. Rectal and vaginal suppositories can be prepared by compression or molding. Typical weights for rectal and vaginal suppositories are about 2 to 3 g.

The pharmaceutical compositions provided herein can be administered ocularly in the form of solutions, suspensions, ointments, lotions, gel forming solutions, powders suitable for solution, gels, ocular inserts, and implants.

The pharmaceutical compositions provided herein can be administered intranasally or by inhalation into the respiratory tract. A pressurized container, pump, spray, atomizer (such as an atomizer that uses electrohydrodynamics to create a fine mist) or nebulizer, either alone or with 1, 1 may be used. A suitable propellant phase combination of 1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane provides a pharmaceutical composition in the form of an aerosol or solution suitable for delivery. The pharmaceutical compositions may also be provided as a dry powder and nasal drops suitable for insufflation, either alone or in combination with an inert carrier such as lactose or phospholipid. For intranasal use, the powder may comprise a bioadhesive agent, including chitosan or cyclodextrin.

A solution or suspension for a pressurized container, pump, sprinkler, nebulizer or nebulizer may be formulated to contain ethanol, an aqueous ethanol solution or to disperse, solubilize, or delay the activity provided herein An alternative agent for the release of the ingredient, a propellant as a solvent; and/or a surfactant such as sorbitan trioleate, oleic acid or oligomeric lactic acid.

The pharmaceutical compositions provided herein can be micronized to a size suitable for delivery by inhalation, such as 50 microns or less, or 10 microns or less. Particles of such sizes can be prepared using comminuting methods known to those skilled in the art, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

Capsules, foaming agents and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mixture of the following: a pharmaceutical composition provided herein; a suitable powder base such as lactose or starch; and a performance modifying agent Such as l -leucine, mannitol or magnesium stearate. Lactose can be anhydrous or in the form of a monohydrate. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical compositions for inhaled/intranasal administration provided herein may further comprise suitable flavors such as menthol and levomentin, or sweeteners such as saccharin or sodium saccharin.

The pharmaceutical compositions provided herein for topical administration can be formulated for immediate release or modified release, including delayed, sustained, pulsed, controlled, targeted, and stylized release.

D. Modified release

The pharmaceutical compositions provided herein can be formulated as modified release dosage forms. As used herein, the term "modified release" refers to a dosage form that has a different rate or location of release of the active ingredient when administered by the same route than an immediate dosage form. Modified release dosage forms include delayed, delayed, prolonged, sustained, pulsatile or pulsed, controlled, accelerated, and rapid, targeted, stylized release, and gastric retention dosage forms. Pharmaceutical compositions of modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate receptors Controlled release devices, ion exchange resins, enteric coatings, multilayer coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient can also be modified by varying the particle size and polymorph of the active ingredient.

Examples of modified release include, but are not limited to, those described in U.S. Patent Nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548. 5,073,543, 5,639,476, 5,354,556, 5,639,480, 5,733,566, 5,739,108, 5,891,474, 5,922,356, 5,972,891, 5,980,945, 5,993,855, 6,045,830, 6,087,324, 6,113,943, 6,197,350, 6,248,363 , Nos. 6,264,970, 6,267,981, 6,376,461, 6,419,961, 6,589,548, 6,613,358, and 6,699,500.

Matrix controlled release device

Pharmaceutical compositions of the modified release dosage forms provided herein can be made using a matrix controlled release device known to those skilled in the art (see Takada et al, "Encyclopedia of Controlled Drug Delivery", Vol. 2, Mathiowitz ed., Wiley, 1999. ).

In one embodiment, the modified release provided herein is formulated using an erosive matrix device that is water swellable, erosive or soluble polymer (including synthetic polymers and naturally occurring polymers and derivatives, such as polysaccharides and proteins). A pharmaceutical composition of the dosage form.

Suitable materials for forming an erosable substrate include, but are not limited to, chitin, chitosan, dextran and amylopectin; agar gum, gum arabic, karaya gum, locust bean gum, tragacanth, carrageen Gum, guar gum, guar gum, sin gum and scleroglucan; starch, such as dextrin and maltodextrin; hydrocolloid, gelatin; phospholipids, such as lecithin; alginate; propylene glycol alginic acid Ester; gelatin; collagen; and celluloses such as ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC) , hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl group Cellulose (HPMC), HPMCP, HPMCAS, hydroxypropylmethylcellulose trimellitate (HPMCAT) and ethylhydroxyethylcellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyacetic acid Vinyl ester; glycerol fatty acid ester; polyacrylamide; polyacrylic acid; copolymer of ethacrylic acid or methacrylic acid (EUDRAGIT ^® , Rohm America, Inc., Piscataway, NJ); poly(2-hydroxyethyl-methacrylate); polylactide; copolymer of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid - Glycolic acid copolymer; poly-D-(-)-3-hydroxybutyric acid; and other acrylic acid derivatives such as butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2 Homopolymers and copolymers of dimethylaminoethyl methacrylate and chlorinated (trimethylaminoethyl) methacrylate.

In another embodiment, the pharmaceutical composition is formulated with a non-erodible matrix device. The active ingredient is dissolved or dispersed in an inert matrix and which, upon administration, is primarily released by diffusion through the inert matrix. Materials suitable for use as non-erodible matrix devices include, but are not limited to, insoluble plastics such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polymethacrylic acid. Butyl ester, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene/propylene copolymer, ethylene/ethyl acrylate copolymer, and vinyl acetate , vinylidene chloride, vinyl chloride copolymer of ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/ethylene Alcohol terpolymer and ethylene/B Alkenyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyoxyxene rubber, polydimethylsiloxane, polyoxycarbonate copolymerization And hydrophilic polymers such as ethyl cellulose, cellulose acetate, cross-linked polyvinylpyrrolidone and cross-linked partially hydrolyzed polyvinyl acetate; and aliphatic compounds such as carnauba wax, microcrystalline wax and glycerol ester.

In a matrix controlled release system, for example, depending on the type of polymer employed, the viscosity of the polymer, the particle size of the polymer and/or active ingredient, the ratio of active ingredient to polymer, and other forms in the composition The agent controls the desired release kinetic profile.

Pharmaceutical compositions of the modified release dosage forms provided herein can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, fused granulation followed by compression.

2. Osmotic controlled release device

Pharmaceutical compositions of the modified release dosage forms provided herein can be made using a osmotic controlled release device comprising a single chamber system, a two chamber system, an asymmetric membrane technology (AMT), and an extruded core system (ECS). Generally, such devices have at least two components: (a) a core containing the active ingredient; and (b) a semipermeable membrane having at least one transfer port and encapsulating the core. The semipermeable membrane controls the inflow of water from the aqueous environment to the core to cause drug release by extrusion through the delivery port.

In addition to the active ingredient, the core of the osmotic device also includes a penetrant as appropriate, which causes a driving force for transporting water from the environment used to the core of the device. A class of penetrants are water soluble, also known as "penetrating polymers" and "hydrogels". Expandable hydrophilic polymers including, but not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG) ), poly(2-hydroxyethyl methacrylate), poly(acrylic acid), poly(methacrylic acid), polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymerization , PVA/PVP copolymer with hydrophobic monomer such as methyl methacrylate and vinyl acetate, hydrophilic polyurethane containing large PEO block, croscarmellose sodium, horn Vegetable gum, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), Sodium alginate, polycarbophil, gelatin, sanxian gum and sodium starch glycolate.

Other classes of penetrants are osmogens, which are capable of absorbing water to affect the osmotic pressure gradient on the barrier of the surrounding coating. Suitable zymogens include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate. Sugar, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose and xylitol; organic acids such as ascorbic acid, benzoic acid, anti Butic acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid and tartaric acid; urea; and mixtures thereof .

Penetrants of different dissolution rates can be used to influence the rate at which the active ingredient is initially delivered from the dosage form. For example, during the first 2 hours you can use something like The amorphous sugar of Mannogeme EZ (SPI Pharma, Lewes, DE) provides a faster delivery to immediately produce the desired therapeutic effect and gradually and continuously releases the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient is released at this rate to replace the amount of the metabolically and excreted active ingredient.

The core may also include various other excipients and carriers as described herein to enhance the efficacy of the dosage form or to aid stability or processing.

Suitable materials for forming semipermeable membranes include various grades of acrylic resins, vinyl compounds, ether compounds, polyamines, polyesters and cellulose derivatives which are water permeable at physiologically relevant pH values. It is not water-soluble or is rendered water-insoluble by chemical changes such as cross-linking. Examples of suitable polymers suitable for forming a coating include plasticized, unplasticized and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA for propionate, cellulose nitrate, cellulose acetate butyrate (CAB), ethyl aminocarbamate CA, CAP, methyl aminocarbamate CA, succinic acid CA, cellulose acetate trimellitate (CAT), dimethylaminoacetic acid CA, ethyl carbonate CA, chlorine Acetic acid CA, ethyl oxalic acid CA, methanesulfonic acid CA, butyl sulfonic acid CA, p-toluenesulfonic acid CA, acetic acid agar, triacetic acid amylose, acetic acid beta glucan, triacetic acid beta glucan, acetaldehyde Acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene-vinyl acetate, EC, PEG, PPG, PEG/PPG copolymer, PVP, HEC, HPC, CMC, CMEC , HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic acid) and esters, and poly(methacrylic acid) and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, Gelatin, polyolefin, polyether, polyfluorene, polyether oxime, polystyrene, polyhalogenated ethylene, polyvinyl ester and ether, natural wax and synthetic wax.

The semipermeable membrane may also be a hydrophobic microporous membrane, wherein the pores are substantially gas-filled and not wetted by the aqueous medium and are permeable to water vapor, as disclosed in U.S. Patent No. 5,798,119. The hydrophobic but water vapor permeable membranes are typically composed of, for example, polyolefins, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polyfluorenes, polyether oximes, polystyrenes, polyhalogenated ethylene. It is composed of polyvinylidene fluoride, polyvinyl ester and ether, natural wax and hydrophobic polymer of synthetic wax.

The transfer opening on the semipermeable membrane can be formed by mechanical or laser perforation after coating. The transfer port can also be formed in situ by eroding the plug of the water soluble material or by rupturing the thinner portion of the film on the indentation in the core. In the case of an asymmetric membrane coating of the type disclosed in U.S. Patent Nos. 5,612,059 and 5,698,220, a transfer port can be formed during the coating process.

The total amount and rate of release of the active ingredient released can be adjusted substantially via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and location of the delivery ports.

The pharmaceutical composition of the osmotic controlled release dosage form may further comprise other conventional excipients as described herein to aid in the performance or processing of the formulation.

Osmotic controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see Remington: The Science and Practi ce of Pharmacy , supra; Santus and Baker, J. Controlled Release 1995, 35, 1-21 Verma et al, Drug Development and Industrial Pharmacy 2000, 26, 695-708; Verma et al, J. Controlled Release 2002, 79, 7-27).

In certain embodiments, the pharmaceutical compositions provided herein are formulated as an AMT controlled release dosage form comprising an asymmetric permeable membrane coated with a core comprising the active ingredient and other pharmaceutically acceptable excipients. See U.S. Patent No. 5,612,059 and WO 2002/17918. AMT controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and dip coating methods.

In certain embodiments, the pharmaceutical compositions provided herein are formulated as an ESC controlled release dosage form comprising a core coated with an active ingredient, hydroxyethyl cellulose, and other pharmaceutically acceptable excipients. Penetration membrane.

3. Multi-particle controlled release device

The pharmaceutical compositions of the modified release dosage forms provided herein can be made using a multiparticulate controlled release device comprising a diameter ranging from about 10 μm to about 3 mm, from about 50 μm to about 2.5 mm, or from about 100 μm to 1 mm. Many particles, particles or pellets. The multiparticulates can be prepared by methods known to those skilled in the art, including wet and dry granulation, extrusion/granulation, roller compaction, melt coagulation, and spraying of seed cores. See, for example, Multiparticulate Oral Drug Delivery ; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology ; Marcel Dekker: 1989.

Other excipients as described herein can be blended with the pharmaceutical composition to aid in processing and formation of multiparticulates. The resulting granules may themselves constitute a multiparticulate device or may be coated with various film forming materials such as enteric polymers, water swellable and water soluble polymers. The multiparticulates can be further processed into capsules or lozenges.

4. Targeted delivery

The pharmaceutical compositions provided herein can also be formulated to target specific tissues, receptors, or other areas of the subject's body to be treated, including liposome-, re-blister-and antibody-based delivery systems. Examples include, but are not limited to, U.S. Patent Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542, and 5,709,874.

Instructions

In one embodiment, there is provided a method of treating, preventing or ameliorating CRTH2 / or more other PGD ₂ receptors and method of a disorder or disease related or one or more symptoms of, or suspected of suffering from which system suffering from such A subject having a condition or disease is administered a therapeutically effective amount of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamide)-benzyl Amine salts of pyrimidin-5-yl}acetic acid or a pharmaceutically acceptable hydrate or solvate thereof or a pharmaceutical composition thereof.

In another embodiment, there is provided a method of treating, preventing or ameliorating of CRTH2 / or more other PGD ₂ receptor regulation and a method for starting the reaction or disease or one or more symptoms of the disorder, comprising administering to a subject having or suspected A subject having such a disease or condition is administered a therapeutically effective amount of one or more of the amine salts or compositions provided herein.

In another embodiment, a method of treating, preventing or ameliorating one or more symptoms of a disease or condition mediated by CRTH2 and/or one or more other PGD ₂ receptors comprising suffering from or suspected of suffering from A subject having such a condition or disease is administered a therapeutically effective amount of one or more of the amine salts or compositions provided herein.

In another embodiment, a method for treating, preventing, or ameliorating one or more symptoms of an eosinophil-associated disease, comprising administering to the subject a therapeutically effective amount of {4,6-double (two An amine salt of methylamino)-2-(4-(4-(trifluoromethyl)benzylidinium)-benzyl)pyrimidin-5-yl}acetic acid or a pharmaceutically acceptable hydrate thereof Or a solvate or a pharmaceutical composition thereof.

In another embodiment, a method for treating, preventing or ameliorating one or more symptoms of a basophil associated disease comprising administering to a subject a therapeutically effective amount of {4,6-double ( An amine salt of dimethylamino)-2-(4-(4-(trifluoromethyl)benzylidinium)-benzyl)pyrimidin-5-yl}acetic acid or a pharmaceutically acceptable hydrate thereof Or a solvate or a pharmaceutical composition thereof.

In another embodiment, a method for treating, preventing or ameliorating one or more symptoms of an inflammatory disease comprising administering to the subject a therapeutically effective amount of {4,6-bis(dimethylamine) An amine salt of 2-(4-(4-(trifluoromethyl)-benzoguanidino)-benzyl)pyrimidin-5-yl}acetic acid or a pharmaceutically acceptable hydrate or solvent thereof A compound or a pharmaceutical composition thereof.

Conditions and diseases that may be treated with one or more of the amine salts provided herein include, but are not limited to, (1) inflammatory or allergic diseases, including systemic and allergic conditions, atopic dermatitis, pityriasis, drugs Allergies, insect bites allergies, food allergies (including celiac disease and the like) and mastocytosis; (2) inflammatory bowel disease, including Crohn's disease, ulcerative colitis, Ileitis and enteritis; (3) vasculitis and shellfish Behcet's syndrome; (4) psoriasis and inflammatory skin diseases, including dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, pityriasis, viral skin lesions (including Human papillomavirus (the disease), HIV or RLV infection, bacterial, fungal and other parasitic skin lesions, and cutaneous lupus erythematosus; (5) asthma and respiratory allergic diseases, including allergic asthma, allergic rhinitis, Otitis media, exercise-induced asthma, allergic conjunctivitis, allergic lung disease and chronic obstructive pulmonary disease; (6) autoimmune diseases, including arthritis (including rheumatoid and psoriatic arthritis), systemic lupus erythematosus, Type 1 diabetes, myasthenia gravis, multiple sclerosis, Graves' disease, and glomerulonephritis; (7) transplant rejection (including allograft rejection and transplantation versus host disease), for example Skin graft rejection, solid organ transplant rejection, bone marrow transplant rejection; (8) fever; (9) cardiovascular disease, including acute heart failure, hypotension, high blood , angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary artery disease, restenosis, and vascular stenosis; (10) cerebrovascular disorders, including traumatic brain injury, stroke, ischemic reperfusion Injury and aneurysm; (11) breast cancer, skin cancer, prostate cancer, cervical cancer, uterine cancer, ovarian cancer, testicular cancer, bladder cancer, lung cancer, liver cancer, laryngeal cancer, oral cancer, colon cancer and gastrointestinal tract (eg esophagus) , stomach, pancreas) cancer, brain cancer, thyroid cancer, blood cancer and lymphatic system cancer; (12) fibrosis, connective tissue disease and sarcoma-like disease; (13) genital and reproductive conditions, including erectile dysfunction; (14) Gastrointestinal disorders, including gastritis, ulcers, nausea, pancreatitis, and vomiting; (15) neurological disorders, including Alzheimer's disease; (16) sleep Sleep disorders, including insomnia, narcolepsy, sleep apnea syndrome and Pickwick Syndrome; (17) pain; (18) kidney disease; (19) eye disease, including glaucoma; and (20) contagious Diseases, including HIV.

In certain embodiments, the disease is selected from the group consisting of asthma, allergic asthma, exercise-induced asthma, allergic rhinitis, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, Contact allergic reaction, contact dermatitis, conjunctivitis, allergic conjunctivitis, eosinophilic bronchitis, food allergy, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, Mast cell hypertrophy, high IgE syndrome, systemic lupus erythematosus, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury, chronic obstructive pulmonary disease, Churg-Strauss syndrome ), sinusitis, basophilic leukemia, chronic urticaria, basophilic leukocytosis, psoriasis, eczema, COPD (chronic obstructive pulmonary disease), arthritis, rheumatoid arthritis, psoriatic arthritis and bones and joints inflammation.

In certain embodiments, the disease is asthma, exercise-induced asthma, allergic rhinitis, atopic dermatitis, chronic obstructive pulmonary disease, or allergic conjunctivitis.

In certain embodiments, the disease is a cookie-synthesis syndrome or sinusitis.

Depending on the disease to be treated and the condition of the subject, the amine salt or composition provided herein may be administered orally, parenterally (eg, intramuscularly, intraperitoneally, intravenously, ICV, intracisternal injection or Infusion, subcutaneous injection or implantation), suction Intravenous, nasal, vaginal, transrectal, sublingual or topical (e.g., transdermal or topical) administration and can be formulated in a suitable dosage unit form or in a pharmaceutically acceptable manner suitable for each route of administration. Agents, adjuvants and vehicles are formulated together. The administration of the amine salt provided herein is also provided in the form of a reservoir formulation wherein the active ingredient is released over a predetermined period of time.

In the treatment, prevention or improvement of asthma, allergic rhinitis, eczema, psoriasis, atopic dermatitis, fever, sepsis, systemic lupus erythematosus, diabetes, rheumatoid arthritis, multiple sclerosis, arteries When atherosclerosis, transplant rejection, inflammatory bowel disease, cancer, or other symptom or condition associated with CRTH2 and/or one or more other PGD ₂ receptors, the appropriate dosage level is usually About 0.001 to 100 mg/kg of patient body weight/day (mg/kg/day), about 0.01 to about 75 mg/kg/day, about 0.1 to about 50 mg/kg/day, about 0.5 to about 25 mg/kg/ Days may range from about 1 to about 20 mg/kg/day, which may be administered in single or multiple doses. Within this range, the dose may be 0.005 to 0.05, 0.05 to 0.5 or 0.5 to 5.0, 1 to 15, 1 to 20 or 1 to 50 mg/kg/day. In certain embodiments, the dosage level is from about 0.001 to 100 mg/kg/day. In certain embodiments, the dosage level is from about 0.01 to about 75 mg/kg/day. In certain embodiments, the dosage level is from about 0.1 to about 50 mg/kg/day. In certain embodiments, the dosage level is from about 0.5 to about 25 mg/kg/day. In certain embodiments, the dosage level is from about 1 to about 20 mg/kg/day.

For oral administration, the pharmaceutical composition may contain from 1.0 to 1,000 mg of active ingredient, especially about 1, about 5, about 10, about 15, about 20, about 25, about 50, about about a symptomatic adjustment of the dosage. 75, about 100, about 150, about A dosage form of 200, about 250, about 300, about 400, about 500, about 600, about 750, about 800, about 900, and about 1,000 mg of the active ingredient is provided to the patient to be treated. The composition can be administered according to a regimen of 1 to 4 times a day, including once, twice, 3 times and 4 times a day.

However, it should be understood that the particular dosage level and dosage frequency may vary for any particular patient and will depend on a variety of factors, including the activity of the particular compound employed, the metabolic stability of the compound and the length of action, age, weight, overall Health status, gender, diet, mode of administration and timing, excretion rate, drug combination, severity of specific conditions, and host undergoing treatment.

Also provided are methods of modulating CRTH2 and/or one or more other PGD ₂ receptors comprising contacting the receptor with one or more amine salts or compositions provided herein. In one embodiment, the receptor is expressed by the cell.

The amine salts provided herein may also be used in combination or in combination with other agents useful in the treatment, prevention or amelioration of one or more of the conditions or conditions in which the amine salts provided herein are useful, including asthma , allergic rhinitis, eczema, psoriasis, atopic dermatitis, fever, sepsis, systemic lupus erythematosus, diabetes, rheumatoid arthritis, multiple sclerosis, atherosclerosis, transplant rejection Inflammatory bowel disease, cancer and their lesions as described above.

The other agents or drugs may be administered simultaneously or sequentially with the amine salts provided herein by the routes and amounts normally employed. When the amine salt provided herein is used together with one or more other drugs, a pharmaceutical composition other than the amine salt provided herein may be used, but this is not necessarily need. Accordingly, the pharmaceutical compositions provided herein include pharmaceutical compositions which, in addition to the amine salts provided herein, also contain one or more additional active ingredients or therapeutic agents.

The weight ratio of amine salt to second active ingredient provided herein can vary and will depend on the effective dose of each ingredient. Typically, the respective effective dose will be used. Thus, for example, when the amine salt provided herein is combined with an NSAID, the weight ratio of amine salt to NSAID provided herein can range from about 1,000:1 to about 1:1,000 or from about 200:1 to about 1:200. . Combinations of the amine salts and other active ingredients provided herein will generally also fall within the above ranges, but in each case an effective amount of each active ingredient should be employed.

Instance

The acid of formula I in the following examples was characterized by nuclear magnetic resonance spectroscopy (NMR), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetry (TGA) and scanning electron microscopy (SEM). Amine salt.

All ¹ H NMR spectra were recorded at 230 MHz using Bruker Instruments NMR unless otherwise stated. The coupling constant (J) is listed in Hertz (Hz) and peaked relative to TMS (δ 0.00 ppm).

X-ray powder diffraction data was recorded on a Rigaku MiniFlex X-ray powder diffractometer (Rigaku Americas, The Woodlands, TX). The radiation is CuKa (40 kV, 40 mA). Data were collected from 3 to 45 degrees 2θ at room temperature at 0.02 degrees per step and 0.6 seconds per step. The sample was prepared as a thin layer of solvent-free powder material on a glass sample holder.

Differential scanning calorimetry was performed using a Mettler 850, TA 2920. The samples were placed in a sealed aluminum pan for analysis with an empty aluminum pan as a reference. in The temperature range of 30 ° C to 280 ° C uses a heating rate of 10 ° C / min.

Thermogravimetric analysis was also performed using a Mettler 850, TA 2920. Place the sample in a ceramic or aluminum sample pan. A heating rate of 20 ° C / min is used in the temperature range of 20 ° C to 600 ° C.

The average particle size of the solid amine salt was determined using scanning electron microscopy.

Example 1 Selection of base for {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylidinium)benzyl)pyrimidin-5-yl}acetate

{4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylidene)-benzyl for 22 pharmaceutically acceptable bases The free acid of pyrimidine-5-yl}acetic acid was screened and the results are summarized in Table 1 along with its water solubility. Among the bases screened, ethylenediamine, piperazine, bisbenzylethylenediamine, and choline each produce a crystalline solid suitable for use in pharmaceutical formulations and as described herein.

Example 2 Preparation of ethylenediamine salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylidinium)benzyl)pyrimidin-5-yl}acetic acid

Heating {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylidinium)-benzyl)pyrimidin-5-yl}acetic acid at reflux temperature (25.2 mg, 0.05 mmol) and a mixture of ethylenediamine (1.68 mg, 0.03 mmol) in ethanol (1.1 mL) gave a clear solution. Then, the clear solution was cooled to room temperature and stirred for additional 2 hours. The precipitate was collected by filtration, washed with 0.5 mL of EtOH / heptane (1:1, v/v) and dried under vacuum at ambient temperature to afford crystals (20.1 mg) (Fig. 5).

The stoichiometry of the ethanolamine salt was determined using ¹ H NMR (Figure 1). The ethylenediamine salt of the acid of formula I contains about 2 moles of acid and 1 mole equivalent of ethylenediamine. For 2 molar equivalents of ethanol, about 1 mole equivalent of ethanol is present in the crystalline salt. The crystalline ethylenediamine salt contains about 4% ethanol. The X-ray powder diffraction pattern of ethylenediamine salt is shown in Figure 2, which has a characteristic XRP diffraction peak at 5.9 Å, expressed as 2θ. This confirmed that the ethylenediamine salt was a crystalline substance.

The differential scanning calorimetry thermal analysis of the ethylenediamine salt is shown in Figure 3. The ethylenediamine salt exhibited an endotherm having a peak temperature of 123.1 °C and an onset temperature of 114.1 °C and a peak temperature of 216.0 °C and an onset temperature of 212.1 °C.

A thermogravimetric analysis thermogram is shown in Figure 4. The ethylenediamine salt showed a slight weight loss up to 75 ° C and showed a 3.951% weight loss between 125 ° C and 150 ° C, which contained about 4% with the crystalline ethylene diamine salt from the ¹ H NMR characterization (Figure 1). The observation of ethanol was consistent.

Other solvent systems were also evaluated for the production of crystalline ethylenediamine salts of the acid of formula I. The results are summarized in Table 2.

Example 3 Preparation of piperazine salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylidinium)benzyl)pyrimidin-5-yl}acetic acid

Heating {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylidinium)-benzyl)pyrimidin-5-yl}acetic acid at reflux temperature (25.0 mg, 0.05 mmol) and a mixture of piperazine (2.38 mg, 0.03 mmol) in ethanol (1.1 mL) gave a clear solution. Then, the clear solution was cooled to room temperature and stirred for additional 2 hours. The precipitate was collected by filtration, washed with 0.5 mL of <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt;

The stoichiometry of the piperazine salt was determined using ¹ H NMR (Figure 6). The piperazine salt of the acid of formula I contains about 2 moles of acid and 1 mole equivalent of piperazine.

The X-ray powder diffraction pattern of the pyridazine salt is shown in Figure 7, which has 20 Characteristic XRP diffraction peaks at 10.7, 15.9, 22.3, and 24.0 表示 are shown. This confirmed that the piperazine salt was a crystalline substance.

A DSC thermal analysis of the piperazine salt is shown in Figure 8. The piperazine salt exhibits a strong endotherm with a peak temperature of 223.2 ° C and an onset temperature of 219.3 ° C and a weak endotherm with a peak temperature of 202.6 ° C and an onset temperature of 198.4 ° C.

A thermogram of the thermogravimetric analysis of the piperazine salt is shown in Figure 9. The ethylenediamine salt showed a slight weight loss up to 75 °C and showed a 3.951% weight loss between 125 and 150 °C.

Other solvent systems were also evaluated for the production of crystalline piperazine salts of the acid of formula I. The results are summarized in Table 3.

Example 4 Preparation of bisbenzyl B of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylidinium)benzyl)pyrimidin-5-yl}acetic acid Diamine salt

Heating {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylidinium)-benzyl)pyrimidin-5-yl}acetic acid at reflux temperature (250.0 mg, 0.5 mmol) and a mixture of bisbenzylethylenediamine (134.4 mg, 0.56 mmol) in ethanol (3.0 mL) afforded a clear solution. Then, the clear solution was cooled to room temperature and stirred for additional 2 hours. Collect the precipitate by filtration to 2 mL IPA/heptane (1:1, v/v) was washed and dried under vacuum to give a rod crystal solid (256.8 mg) (Figure 14).

The stoichiometry of the dibenzylethylenediamine salt was determined using ¹ H NMR (Figure 11). The bisbenzylethylenediamine salt of the acid of formula I contains about 2 moles of acid and 1 mole equivalent of bisbenzylethylenediamine.

The X-ray powder diffraction pattern of the bisbenzylethylenediamine salt is shown in Figure 12, which has a characteristic XRP diffraction peak at 8.0, 11.5, 16.0, 17.5, and 23.4 Å, expressed as 2θ. This confirmed that the bisbenzylethylenediamine salt was a crystalline substance.

A DSC thermal analysis of the bisbenzylethylenediamine salt is shown in Figure 13. The bisbenzylethylenediamine salt exhibited a strong endotherm with a peak temperature of 155.8 °C and an onset temperature of 154.2 °C.

Example 5 Preparation of choline salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylidinium)benzyl)pyrimidin-5-yl}acetic acid

Heating {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylidinium)-benzyl)pyrimidin-5-yl}acetic acid at reflux temperature (249.5 mg, 0.5 mmol) and a mixture of choline (69.4 mg, 0.58 mmol) in IPA (3.5 mL) gave a clear solution. Then, the resulting clear solution was cooled to room temperature and stirred for additional 2 hours. The precipitate was collected by filtration, washed with 2 mL of IPA / heptane (1:1, v/v) and dried under vacuum at ambient temperature to afford a rod-like and rhodium crystalline solid (232 mg) (Figure 19).

The stoichiometry of the choline salt was determined using ¹ H NMR (Figure 15). The choline salt of the acid of formula I contains about 1 mole equivalent of acid and 1 mole equivalent of choline.

An X-ray powder diffraction pattern of choline salt is shown in Fig. 16, which has 2θ represents the characteristic XRP diffraction peak at 6.5, 19.6, 20.0, 21.9, and 26.4 。. This confirmed that the choline salt was a crystalline substance.

A DSC thermal analysis of the choline salt is shown in Figure 17. The choline salt exhibited a strong endotherm with a peak temperature of 194.8 °C and an onset temperature of 192.6 °C.

A thermogram of the thermogravimetric analysis of the choline salt is shown in FIG. The choline salt showed almost no weight loss up to 200 °C.

Other solvent systems were also evaluated for the production of crystalline choline salts of the acid of formula I. The results are summarized in Table 4.

Example 6 Competitive radioligand binding assay

Evaluation of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoro)) provided herein using a competitive radioligand binding assay to express stable transfected cell lines of CRTH2 or DPI The binding affinity and selectivity of the amine salt of benzhydrazinyl)benzyl)pyrimidin-5-yl}acetic acid.

Prostaglandin D ₂ and 13,14-dihydro-15-one PGD ₂ were obtained from Cayman Chemical (Ann Arbor, MI). Having a specific activity 160 Ci / mmol of radiolabeled ^{_{PGD 2 (5,6,8,9,12,14,15- 3 H (N}} )) lines were obtained from PerkinElmer (Boston, MA). Cell culture medium RPMI 1640, HEPES buffer, phosphate buffered saline (PBS), L-glutamine and penicillin-streptomycin solutions were obtained from Mediatech Inc. (Herndon, VA). Fetal bovine serum (FCS) was obtained from Cambrex (Walkersville, MD). The puromycin system was obtained from Invitrogen (San Diego, CA). Poly(ethyleneimine) (PEI) was obtained from Acros Organics (Morris Plains, NJ). Purified individual rat anti-human CRTH2 antibody (BM16), rat IgG2a, κ (pure line R35-95) and goat anti-rat Ig-FITC line were obtained from Becton Dickinson Biosciences (San Diego, CA). BSA (Fraction V) and sodium azide are obtained from Sigma Chemical Company (St. Louis).

CRTH2 and DPI stable cell lines were generated according to the procedure described by Sugimoto et al. ( J. Pharm. Exp. Therap . 2003, 305, 347-352). These cell lines were maintained in HEPES buffer (25 mM), FCS (10%), L-glutamine (2 mM), penicillin (10 IU/mL), streptomycin (100 μg/mL). And rutheniummycin (1 μg/mL) in RPMI 1640 medium.

The surface appearance of CRTH2 on transfected cell lines was monitored periodically during culture and prior to each competitive radioligand binding assay. CRTH2 expressing cells and untransfected cells were incubated for 15 minutes on ice with purified anti-CRTH2 antibody (pure line BM16) or isotype control antibody (rat IgG2a, κ). The cells were then washed in 2 mL FACS buffer (PBS containing 1% BSA (Fraction V) and 0.1% sodium azide). The cells were then incubated with FITC conjugated anti-rat antibody (goat anti-rat Ig-FITC) on ice. After washing in cold FACS buffer, cells were analyzed using a FACScan II analyzer from Becton Dickinson (Mountain View, CA) and CellQuest software.

Such as (Sugimoto et al,J. Pharm. Exp. Therap . 2003, 305, 347-352; Sugimoto et al.Eur. J. Pharmacol .2005, 524, 30-37) The response is also reflected in the PGD by direct measurement₂ Calcium mobilization to assess The functionality of transfectants.

Radioligand binding assays were performed according to the method of Sugimoto et al. ( J. Pharm. Exp. Therap. 2003, 305, 347-352; Eur. J. Pharmacol. 2005, 524, 30-37). The test compound was dissolved in DMSO at a concentration of 100 mM as a stock solution. Serial dilutions were prepared from 10 μM in binding buffer prior to assay. The transfected cells were resuspended in binding buffer (50 mM Tris-HCl, 40 mM MgCl ₂ and 0.1% bovine serum albumin, pH 7.4) at a concentration of 4 × 10 ⁶ /mL at room temperature. Next, transfection was performed by adding 50 μL of cell suspension, followed by addition of 10 μL of ³ H-PGD ₂ , 10 μL of a concentration of test compound solution or control, 30 μL of binding buffer to a final volume of 100 μL. The cells were seeded in U-bottom polypropylene 96-well plates (Fisher). The final concentration of ³ H-PGD ₂ in each well was 1 nM. After incubation for 1 hour at room temperature with gentle shaking, the cell suspension was transferred to a filter plate (Millipore, MA) pre-wetted with 0.5% PEI buffer. The cell pellet was washed 3 times with binding buffer and the plate was allowed to air dry. Scintillator ^{(50 μL; Microscint TM 20,} Perkin Elmer, Boston, MA) was added to each well and using TopCount (Packard Bioscience, Meriden, CT ) measurement of radioactivity. Use Prizm ^TM graphics program (GraphPad Software Inc., San Diego, CA) data analysis. As shown in Figures 20 and 21, {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylideneamino)benzyl)pyrimidine of formula I -5-yl}acetic acid and its pharmaceutically acceptable salts have high affinity for CRTH2 and selectively bind CRTH2.

The examples set forth above are provided to provide a complete disclosure and illustration of how to make and utilize such embodiments, and such examples are It is not intended to limit the scope of this disclosure. Modifications to the above-described modes for implementing the present disclosure that are apparent to those skilled in the art are intended to fall within the scope of the following claims. All publications, patents, and patent applications cited in this specification are hereby incorporated by reference to the extent of The way is incorporated in this document in general.

Figure 1 shows {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)-benzylidino)benzyl)-pyrimidin-5-yl of formula I } Proton nuclear magnetic resonance ( ¹ H NMR) spectrum of crystalline ethylenediamine salt of acetic acid.

Figure 2 shows an X-ray powder (XRP) diffraction pattern of the crystalline ethylenediamine salt of the acid of formula I.

Figure 3 shows a differential scanning calorimetry (DSC) thermogram of the crystalline ethylenediamine salt of the acid of Formula I.

Figure 4 shows a thermogravimetric (TG) thermogram of the crystalline ethylenediamine salt of the acid of Formula I.

Figure 5 shows a scanning electron microscope (SEM) photograph of the crystalline ethylenediamine salt of the acid of Formula I.

Figure 6 shows the ¹ H NMR spectrum of the crystalline piperazine salt of the acid of Formula I.

Figure 7 shows an XRP diffraction pattern of the crystalline piperazine salt of the acid of Formula I.

Figure 8 shows a DSC thermogram of the crystalline piperazine salt of the formula I.

Figure 9 shows a TG thermogram of the crystalline piperazine salt of the acid of Formula I.

Figure 10 shows a SEM photograph of the crystalline piperazine salt of the acid of Formula I.

Figure 11 shows the ¹ H NMR spectrum of the crystalline bisbenzylethylenediamine salt of the acid of formula I.

Figure 12 shows an XRP diffraction pattern of the crystalline crystalline bisbenzylethylenediamine salt of Formula I.

Figure 13 shows a DSC thermogram of the crystalline bisbenzylethylenediamine salt of the acid of Formula I.

Figure 14 shows an SEM photograph of the crystalline crystalline bisbenzylethylenediamine salt of formula I.

Figure 15 shows the ¹ H NMR spectrum of the crystalline choline salt of the acid of Formula I.

Figure 16 shows an XRP diffraction pattern of the crystalline choline salt of the acid of Formula I.

Figure 17 shows a DSC thermogram of the crystalline choline salt of the acid of Formula I.

Figure 18 shows a TG thermogram of the crystalline choline salt of the acid of Formula I.

Figure 19 shows an SEM photograph of the crystalline choline salt of the acid of Formula I.

Figure 20 shows (4,6-bis(dimethylamino)-2-(4-(4-trifluoromethyl)) of formula I obtained using CRTH2 transfected cells in a competitive radioligand binding assay. Dosage response curve for benzamidine)benzyl)pyrimidin-5-yl}acetic acid.

Figure 21 shows {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)) of formula I, obtained using DP1 transfected cells in a competitive radioligand binding assay. Benzylamino)benzyl)pyrimidin-5-yl}acetic acid (▲) together with the DP1 selective antagonist for comparison, BWA 868C ( Dose response curve.

(no component symbol description)

Claims (46)

a crystalline form of a salt comprising ethylenediamine and {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylideneamino)benzyl of formula I Pyrimidine-5-yl}acetic acid: The peak of the X-ray powder diffraction pattern expressed in 2θ appears at about 5.9°. As the salt of claim 1, the DSC thermogram showed an endothermic peak temperature at about 123 ° C and an onset temperature of about 114 °C. As the salt of claim 1, the DSC thermogram showed an endothermic peak temperature at about 216 ° C and an onset temperature of about 212 °C. The salt of claim 1 which has a water solubility of about 6 mg/mL at 25 °C. The salt of claim 1 which comprises about 2 moles of acid of formula I and about 1 mole equivalent of ethylenediamine. The salt of claim 1, which has an X-ray powder diffraction pattern substantially as shown in FIG. A salt of claim 1 having a differential scanning calorimetry thermogram substantially as shown in FIG. a crystalline form of a salt comprising piperazine and {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylideneamino)benzyl of formula I Pyrimidine-5-yl}acetic acid: The peak of the X-ray powder diffraction pattern represented by 2θ appears at about 10.7, 15.9, 22.3 or 24.0°. A salt according to claim 8 which comprises about 2 moles of an acid of formula I and about 1 mole equivalent of piperazine. The salt of the salt of claim 8 has a DSC thermogram showing an endothermic peak temperature at about 203 ° C and an onset temperature of about 198 ° C. As the salt of claim 8, the DSC thermogram showed an endothermic peak temperature at about 223 ° C and an onset temperature of about 219 °C. The salt of claim 8 which has a water solubility of about 5 mg/mL at 25 °C. The salt of claim 8, which has an X-ray powder diffraction pattern substantially as shown in FIG. A salt of claim 8 having a differential scanning calorimetry thermogram substantially as shown in FIG. a crystalline form of a salt comprising bisbenzylethylenediamine and {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamide) of formula I Benzyl)pyrimidin-5-yl}acetic acid: The peak of the X-ray powder diffraction pattern expressed in 2θ appears at about 8.0, 11.5, 16.0, 17.5 or 23.4°. A salt according to claim 15 which comprises about 2 moles of an acid of formula I and about 1 mole equivalent of bisbenzylethylenediamine. As with the salt of claim 15, the DSC thermogram showed an endothermic peak temperature at about 156 °C and an onset temperature of about 154 °C. The salt of claim 15 which has a water solubility at 25 ° C of about 0.08 mg/mL. The salt of claim 15 having an X-ray powder diffraction pattern substantially as shown in FIG. A salt of claim 15 having a differential scanning calorimetry thermogram substantially as shown in FIG. a crystalline form of a salt comprising choline and a {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzylideneamino)benzyl group of formula I Pyrimidine-5-yl}acetic acid: The peak of the X-ray powder diffraction pattern represented by 2θ appears at about 6.5, 19.6, 20.0, 21.9 or 26.1°. The salt of claim 21 which comprises about 1 mole equivalent of the acid of formula I and about 1 mole equivalent of choline. As the salt of claim 21, its DSC thermogram showed an endothermic peak temperature at about 195 °C and an onset temperature of about 193 °C. The salt of claim 21, which has a water solubility of about 24 mg/mL at 25 °C. A salt according to claim 21, which has an X-ray substantially as shown in FIG. Powder diffraction pattern. A salt of claim 21 having a differential scanning calorimetry thermogram substantially as shown in FIG. A pharmaceutical composition comprising a salt according to any one of claims 1 to 26 and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition of claim 27, wherein the composition is formulated for oral, nasal, transbronchial or topical administration. The pharmaceutical composition of claim 27 or 28, wherein the composition is formulated as a single dosage form. Use of a salt according to any one of claims 1 to 26, or a pharmaceutical composition according to any one of claims 27 to 29, for the manufacture of one or more of the treatment, prevention or amelioration of a CRTH2-mediated disease Symptoms of medicine. A use of a salt according to any one of claims 1 to 26, or a pharmaceutical composition according to any one of claims 27 to 29, for use in the preparation of a treatment, prevention or amelioration of an eosinophil-associated disease A variety of medical products. A use of a salt according to any one of claims 1 to 26, or a pharmaceutical composition according to any one of claims 27 to 29, for use in the preparation of a medicament for the treatment, prevention or amelioration of a basophil associated disease Or a variety of symptoms of medicine. Use of a salt according to any one of claims 1 to 26, or a pharmaceutical composition according to any one of claims 27 to 29, for the treatment, prevention or amelioration of one or more symptoms of an inflammatory disease Pharmaceutical products. The use of any one of claims 30 to 33, wherein the disease is selected from the group consisting of Groups of: asthma, allergic asthma, exercise-induced asthma, allergic rhinitis, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact allergic reactions, contact dermatitis, conjunctivitis, Allergic conjunctivitis, eosinophilic bronchitis, food allergy, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, mastocytosis, high IgE Syndrome, systemic lupus erythematosus, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury, chronic obstructive pulmonary disease, Churg-Strauss syndrome, sinusitis, alkalophilic Sexual cell leukemia, chronic urticaria, basophilic leukocytosis, psoriasis, eczema, COPD (chronic obstructive pulmonary disease), arthritis, rheumatoid arthritis, psoriatic arthritis and osteoarthritis. The use of any one of claims 30 to 33, wherein the disease is asthma, exercise-induced asthma, allergic rhinitis, atopic dermatitis, chronic obstructive pulmonary disease or allergic conjunctivitis. The use of any one of claims 30 to 33, wherein the disease is a cookie-synthesis syndrome or sinusitis. A method for the preparation of a salt according to any one of claims 1 to 26, which comprises making {4,6-bis(dimethylamino)-2-(4-(4-) at a first predetermined temperature (Trifluoromethyl)benzhydrylamino)benzyl)pyrimidin-5-yl}acetic acid is reacted with the amine in a solvent. The method of claim 37, further comprising precipitating the salt at a second predetermined temperature. A method for the preparation of a salt according to any one of claims 1 to 26, which comprises the steps of: (a) by making {4,6-bis(dimethylamino)- at a first predetermined temperature 2-(4-(4-(trifluoromethyl)benzylidinium)benzyl)pyrimidin-5-yl}acetic acid is reacted with the amine in a solvent to produce the amine salt; and (b) in the second The amine salt is precipitated at a predetermined temperature. The method of any one of claims 37 to 39, wherein the first temperature is from about -10 to about 150 °C. The method of any one of clauses 37 to 39, wherein the first temperature is about 20 to 100 °C. The method of claim 38 or 39, wherein the second temperature is between about -50 and 50 °C. The method of claim 38 or 39, wherein the second temperature is between about -23 and 35 °C. The method of claim 39, wherein the solvent is selected from the group consisting of methanol, ethanol, isopropanol, propanol, tetrahydrofuran, water, and mixtures thereof. The method of any one of clauses 37 to 39, wherein an anti-solvent is added in the precipitation step to produce a precipitate. The method of claim 45, wherein the anti-solvent is selected from the group consisting of water, alkanes, ethers, aromatic hydrocarbons, and mixtures thereof.